scholarly journals LUBAC: a new player in polyglucosan body disease

2021 ◽  
Author(s):  
Andrew Aboujaoude ◽  
Berge Minassian ◽  
Sharmistha Mitra
Keyword(s):  
Adaptor Protein ◽  
Glycogen Metabolism ◽  
Therapeutic Approaches ◽  
Ubiquitin Chain ◽  
Polyglucosan Bodies ◽  
Cell Death Pathways ◽  
Protein Ubiquitination ◽  
Polyglucosan Body ◽  
Severe Immunodeficiency ◽  
Near Future

Altered protein ubiquitination is associated with the pathobiology of numerous diseases; however, its involvement in glycogen metabolism and associated polyglucosan body (PB) disease has not been investigated in depth. In PB disease, excessively long and less branched glycogen chains (polyglucosan bodies, PBs) are formed, which precipitate in different tissues causing myopathy, cardiomyopathy and/or neurodegeneration. Linear ubiquitin chain assembly complex (LUBAC) is a multi-protein complex composed of two E3 ubiquitin ligases HOIL-1L and HOIP and an adaptor protein SHARPIN. Together they are responsible for M1-linked ubiquitination of substrates primarily related to immune signaling and cell death pathways. Consequently, severe immunodeficiency is a hallmark of many LUBAC deficient patients. Remarkably, all HOIL-1L deficient patients exhibit accumulation of PBs in different organs especially skeletal and cardiac muscle resulting in myopathy and cardiomyopathy with heart failure. This emphasizes LUBAC's important role in glycogen metabolism. To date, neither a glycogen metabolism-related LUBAC substrate nor the molecular mechanism are known. Hence, current reviews on LUBAC's involvement in glycogen metabolism are lacking. Here, we aim to fill this gap by describing LUBAC's involvement in PB disease. We present a comprehensive review of LUBAC structure, its role in M1-linked and other types of atypical ubiquitination, PB pathology in human patients and findings in new mouse models to study the disease. We conclude the review with recent drug developments and near-future gene-based therapeutic approaches to treat LUBAC related PB disease.

scholarly journals OTUD1 deubiquitylase regulates NF-κB- and KEAP1-mediated inflammatory responses and reactive oxygen species-associated cell death pathways

2021 ◽  
Author(s):  
Daisuke Oikawa ◽  
Min Gi ◽  
Hidetaka Kosako ◽  
Kouhei Shimizu ◽  
Hirotaka Takahashi ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Stress Responses ◽  
Inflammatory Responses ◽  
Reactive Oxygen ◽  
Antioxidant Response ◽  
Oxygen Species ◽  
Ubiquitin Chain ◽  
Intrinsically Disordered ◽  
Cell Death Pathways

Deubiquitylating enzymes (DUBs) regulate numerous cellular functions by removing ubiquitin modifications. We examined the effects of 88 human DUBs on linear ubiquitin chain assembly complex (LUBAC)-induced NF-κB activation, and identified OTUD1 as a potent suppressor. OTUD1 regulates the canonical NF-κB pathway by hydrolysing K63-linked ubiquitin chains from NF-κB signalling factors, including LUBAC. OTUD1 negatively regulates the canonical NF-κB activation, apoptosis, and necroptosis, whereas OTUD1 upregulates the interferon (IFN) antiviral pathway. The N-terminal intrinsically disordered region of OTUD1, which contains an EGTE motif, is indispensable for KEAP1-binding and NF-κB suppression. OTUD1 is involved in the KEAP1-mediated antioxidant response and reactive oxygen species (ROS)-induced cell death, oxeiptosis. In Otud1-/--mice, inflammation, oxidative damage, and cell death were enhanced in inflammatory bowel disease, acute hepatitis, and sepsis models. Thus, OTUD1 is a crucial regulator for the inflammatory, innate immune, and oxidative stress responses and ROS-associated cell death pathways.

New insights of CRISPR technology in human pathogenic fungi

2019 ◽  
Vol 14 (14) ◽  
pp. 1243-1255 ◽  
Author(s):  
Elvira Román ◽  
Daniel Prieto ◽  
Rebeca Alonso-Monge ◽  
Jesús Pla
Keyword(s):  
Mammalian Cells ◽  
Genetic Manipulation ◽  
Pathogenic Fungi ◽  
Biological Research ◽  
Therapeutic Approaches ◽  
New Therapeutic Approaches ◽  
Short Palindromic Repeat ◽  
Future Outcomes ◽  
Near Future ◽  
Genome Manipulation

Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-Cas systems have emerged as a powerful tool for genome manipulation. Class 2 type II CRISPR/ CAS9 is so far the most studied system and has been implemented in many biological systems such as mammalian cells, plants, fungi and bacteria. Fungi are important causes of human diseases worldwide. Genetic manipulation of pathogenic fungi is critical to develop new therapeutic approaches and novel antifungals. We will review here the progress done with CRISPR/ CAS9 systems in human pathogenic fungi, with emphasis in Candida albicans and the main modifications that have improved their usefulness in biological research. We finally discuss possible future outcomes and applications to the developed in a near future.

scholarly journals Essential role of the linear ubiquitin chain assembly complex and TAK1 kinase in A20 mutant Hodgkin lymphoma

2020 ◽  
Vol 117 (46) ◽  
pp. 28980-28991
Author(s):  
Zhihui Song ◽  
Wei Wei ◽  
Wenming Xiao ◽  
Essel D. Al-Saleem ◽  
Reza Nejati ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Strong Support ◽  
Ubiquitin Chain ◽  
Guide Rna ◽  
Barr Virus ◽  
Protein Ubiquitination ◽  
Crispr Screen ◽  
Epstein Barr

More than 70% of Epstein–Barr virus (EBV)-negative Hodgkin lymphoma (HL) cases display inactivation of TNFAIP3 (A20), a ubiquitin-editing protein that regulates nonproteolytic protein ubiquitination, indicating the significance of protein ubiquitination in HL pathogenesis. However, the precise mechanistic roles of A20 and the ubiquitination system remain largely unknown in this disease. Here, we performed high-throughput CRISPR screening using a ubiquitin regulator-focused single-guide RNA library in HL lines carrying either wild-type or mutant A20. Our CRISPR screening highlights the essential oncogenic role of the linear ubiquitin chain assembly complex (LUBAC) in HL lines, which overlaps with A20 inactivation status. Mechanistically, LUBAC promotes IKK/NF-κB activity and NEMO linear ubiquitination in A20 mutant HL cells, which is required for prosurvival genes and immunosuppressive molecule expression. As a tumor suppressor, A20 directly inhibits IKK activation and HL cell survival via its C-terminal linear-ubiquitin binding ZF7. Clinically, LUBAC activity is consistently elevated in most primary HL cases, and this is correlated with high NF-κB activity and low A20 expression. To further understand the complete mechanism of NF-κB activation in A20 mutant HL, we performed a specifically designed CD83-based NF-κB CRISPR screen which led us to identify TAK1 kinase as a major mediator for NF-κB activation in cells dependent on LUBAC, where the LUBAC-A20 axis regulates TAK1 and IKK complex formation. Finally, TAK1 inhibitor Takinib shows promising activity against HL in vitro and in a xenograft mouse model. Altogether, these findings provide strong support that targeting LUBAC or TAK1 could be attractive therapeutic strategies in A20 mutant HL.

Tu1996 Glycogen Metabolism Defects Produce Gastrointestinal Myopathy With Polyglucosan Bodies

2012 ◽  
Vol 142 (5) ◽  
pp. S-897
Author(s):  
Yasotha Duraisamy ◽  
Milly West ◽  
Charles H. Knowles ◽  
Hasan O. Akman ◽  
Salvatore DiMauro ◽  
...  
Keyword(s):  
Glycogen Metabolism ◽  
Polyglucosan Bodies

Therapeutic targets in liver fibrosis

2011 ◽  
Vol 300 (5) ◽  
pp. G709-G715 ◽  
Author(s):  
Jonathan A. Fallowfield
Keyword(s):  
Liver Fibrosis ◽  
Molecular Mechanisms ◽  
Treatment Strategies ◽  
Market Potential ◽  
Therapeutic Approaches ◽  
The Us ◽  
Exciting Potential ◽  
Definition Of ◽  
And Function ◽  
Near Future

Detailed analysis of the cellular and molecular mechanisms that mediate liver fibrosis has provided a framework for therapeutic approaches to prevent, slow down, or even reverse fibrosis and cirrhosis. A pivotal event in the development of liver fibrosis is the activation of quiescent hepatic stellate cells (HSCs) to scar-forming myofibroblast-like cells. Consequently, HSCs and the factors that regulate HSC activation, proliferation, and function represent important antifibrotic targets. Drugs currently licensed in the US and Europe for other indications target HSC-related components of the fibrotic cascade. Their deployment in the near future looks likely. Ultimately, treatment strategies for liver fibrosis may vary on an individual basis according to etiology, risk of fibrosis progression, and the prevailing pathogenic milieu, meaning that a multiagent approach could be required. The field continues to develop rapidly and starts to identify exciting potential targets in proof-of-concept preclinical studies. Despite this, no antifibrotics are currently licensed for use in humans. With epidemiological predictions for the future prevalence of viral, obesity-related, and alcohol-related cirrhosis painting an increasingly gloomy picture, and a shortfall in donors for liver transplantation, the clinical urgency for new therapies is high. There is growing interest from stakeholders keen to exploit the market potential for antifibrotics. However, the design of future trials for agents in the developmental pipeline will depend on strategies that enable equal patient stratification, techniques to reliably monitor changes in fibrosis over time, and the definition of clinically meaningful end points.

scholarly journals Adaptor protein Lnk negatively regulates the mutant MPL, MPLW515L associated with myeloproliferative disorders

Blood ◽  
2007 ◽  
Vol 110 (9) ◽  
pp. 3360-3364 ◽  
Author(s):  
Sigal Gery ◽  
Saskia Gueller ◽  
Katya Chumakova ◽  
Norihiko Kawamata ◽  
Liqin Liu ◽  
...  
Keyword(s):  
Leukemia Virus ◽  
Adaptor Protein ◽  
Myeloproliferative Disorders ◽  
Sh2 Domain ◽  
Negative Regulator ◽  
Wild Type ◽  
Therapeutic Approaches ◽  
Downstream Signaling ◽  
Cellular Pathways ◽  
Insight Into

Abstract Recently, activating myeloproliferative leukemia virus oncogene (MPL) mutations, MPLW515L/K, were described in myeloproliferative disorder (MPD) patients. MPLW515L leads to activation of downstream signaling pathways and cytokine-independent proliferation in hematopoietic cells. The adaptor protein Lnk is a negative regulator of several cytokine receptors, including MPL. We show that overexpression of Lnk in Ba/F3-MPLW515L cells inhibits cytokine-independent growth, while suppression of Lnk in UT7-MPLW515L cells enhances proliferation. Lnk blocks the activation of Jak2, Stat3, Erk, and Akt in these cells. Furthermore, MPLW515L-expressing cells are more susceptible to Lnk inhibitory functions than their MPL wild-type (MPLWT)–expressing counterparts. Lnk associates with activated MPLWT and MPLW515L and colocalizes with the receptors at the plasma membrane. The SH2 domain of Lnk is essential for its binding and for its down-regulation of MPLWT and MPLW515L. Lnk itself is tyrosine-phosphorylated following thrombopoietin stimulation. Further elucidating the cellular pathways that attenuate MPLW515L will provide insight into the pathogenesis of MPD and could help develop specific therapeutic approaches.

Mapping of Purkinje Neuron Loss and Polyglucosan Body Accumulation in Hereditary Cerebellar Degeneration in Scottish Terriers

2011 ◽  
Vol 49 (5) ◽  
pp. 852-859 ◽  
Author(s):  
G. Urkasemsin ◽  
K. E. Linder ◽  
J. S. Bell ◽  
A. de Lahunta ◽  
N. J. Olby
Keyword(s):  
Periodic Acid ◽  
Cell Loss ◽  
Significant Loss ◽  
Purkinje Neurons ◽  
Periodic Acid Schiff ◽  
Polyglucosan Bodies ◽  
Polyglucosan Body ◽  
Degenerative Disorder ◽  
Neurofilament 200 ◽  
Scottish Terriers

A hereditary cerebellar degenerative disorder has emerged in Scottish Terriers. The aims of this study were to describe and quantify polyglucosan body accumulation and quantify Purkinje neurons in the cerebellum of affected and control dogs. The brains of 6 affected Scottish Terriers ranging in age from 8 to 15 years and 8 age-matched control dogs were examined histopathologically. Counts of Purkinje neurons and polyglucosan bodies were performed in control and affected dogs on cerebellar sections stained with periodic acid–Schiff. Affected dogs showed a significant loss of Purkinje neurons compared with control dogs (vermis: P < .0001; hemisphere: P = .0104). The degeneration was significantly more pronounced dorsally than ventrally ( P < .0001). There were significantly more polyglucosan bodies in the ventral half of the vermis when compared with the dorsal half ( P < .0001) in affected dogs. In addition, there were more polyglucosan bodies in the ventral half of the vermis in affected dogs than in control dogs ( P = .0005). Polyglucosan bodies in all affected dogs stained positively with toluidine blue and alcian blue. Immunohistochemically, polyglucosan bodies in affected dogs were positive for neurofilament 200 kD and ubiquitin and negative for glial fibrillary acidic protein, synaptophysin, neurospecific enolase, vimentin, and S100; the bodies were negative for all antigens in control dogs. Ultrastructurally, polyglucosan bodies in 1 affected dog were non–membrane-bound, amorphous structures with a dense core. This study demonstrates significant Purkinje cell loss and increased polyglucosan bodies in the cerebellum of affected Scottish Terriers.

scholarly journals TNF receptor signalling in autoinflammatory diseases

2019 ◽  
Vol 31 (10) ◽  
pp. 639-648 ◽  
Author(s):  
Heledd H Jarosz-Griffiths ◽  
Jonathan Holbrook ◽  
Samuel Lara-Reyna ◽  
Michael F McDermott
Keyword(s):  
Molecular Mechanisms ◽  
Innate Immune ◽  
Autoinflammatory Diseases ◽  
Tumour Necrosis Factor Receptor ◽  
Therapeutic Approaches ◽  
Ubiquitin Chain ◽  
Receptor Signalling ◽  
Target Disease ◽  
Necrosis Factor ◽  
Disease Present

Abstract Autoinflammatory syndromes are a group of disorders characterized by recurring episodes of inflammation as a result of specific defects in the innate immune system. Patients with autoinflammatory disease present with recurrent outbreaks of chronic systemic inflammation that are mediated by innate immune cells, for the most part. A number of these diseases arise from defects in the tumour necrosis factor receptor (TNFR) signalling pathway leading to elevated levels of inflammatory cytokines. Elucidation of the molecular mechanisms of these recently defined autoinflammatory diseases has led to a greater understanding of the mechanisms of action of key molecules involved in TNFR signalling, particularly those involved in ubiquitination, as found in haploinsufficiency of A20 (HA20), otulipenia/OTULIN-related autoinflammatory syndrome (ORAS) and linear ubiquitin chain assembly complex (LUBAC) deficiency. In this review, we also address other TNFR signalling disorders such as TNFR-associated periodic syndrome (TRAPS), RELA haploinsufficiency, RIPK1-associated immunodeficiency and autoinflammation, X-linked ectodermal dysplasia and immunodeficiency (X-EDA-ID) and we review the most recent advances surrounding these diseases and therapeutic approaches currently used to target these diseases. Finally, we explore therapeutic advances in TNF-related immune-based therapies and explore new approaches to target disease-specific modulation of autoinflammatory diseases.

Prospects in treatment of multiple sclerosis: near future

2020 ◽  
Vol 28 (3) ◽  
pp. 377-390
Author(s):  
Gennadii E. Sheiko ◽  
Anna N. Belova ◽  
Maksim N. Kudykin
Keyword(s):  
Multiple Sclerosis ◽  
Modern Science ◽  
Therapeutic Approaches ◽  
New Methods ◽  
New Therapeutic Approaches ◽  
The Central Nervous System ◽  
Unclear Etiology ◽  
Near Future ◽  
The Given ◽  
Methods Of Treatment

Multiple sclerosis (MS) is a widespread dysimmune-neurodegenerative disease of the central nervous system of unclear etiology. Despite significant achievements in the therapy of MS, the level of progressing disability and early mortality remains alarmingly high. The main aim of the given review is to give a detailed description of new promising medical drugs for treatment of MS. In the article the data of preclinical and clinical trials are given, presumptive mechanisms of the medical drugs under development are described. Development of new therapeutic approaches in treatment of MS is of great interest in modern science. The given review highlights new methods of treatment that are now undergoing clinical trialы and will probably come to the clinical practice in the near future.

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